Normal angiogenesis is required in many physiological conditions such as wound healing, female reproduction, and fetal development. Abnormal or pathological angiogenesis has been implicated in neoplastic diseases including solid tumor growth, metastasis, and Kaposi's sarcoma; various eye diseases including diabetic retinopathy, and macular degeneration; inflammatory conditions including rheumatoid arthritis, and osteoarthritis; skin diseases including psoriasis, eczema, and scleroderma; as well as ulcerative colitis and childhood haemangiomas (Toi et. al., 1995, Breast Cancer Res. and Treat., 192-204; Holmgren et. al., 1995, Nature Medicine, 149-153; Folkman, 1995, Nature Medicine, 27-31; Jackson et. al., 1997, FASEB J., 457-465). Several growth factors have been implicated in the angiogenesis process including basic and acidic fibroblast growth factor (bFGF and aFGF), transforming growth factor (TGF), and vascular endothelial growth factor (VEGF)(Seed, 1996, Exp. Opin. Invest. Drugs, 1617-1637; Colville-Nash et. al., 1997, Mol. Med. Today, 14-23).
VEGF receptors are localized to endothelial cells in contrast to the other growth factors described above. In addition, VEGF has the unique ability to induce vascular permeability (VEGF was first described as vascular permeability factor) as well as serve as a survival factor for newly developed blood vessels (Yaun et. al., 1996, 14765-14770, Proc. Nat. Acad. Sci). These properties, in addition to its mitogenic effects, makes VEGF a critical target in pathological diseases that require neovascularization. Inhibition of VEGF function has been shown to inhibit disease progression in tumors (Borgstrom et. al., Cancer Res., 1996, 4032-4039; Kim, et. al., 1993, Nature, 841-844) and retinal neovascularization (Aiello et. al., 1995, Proc. Nat. Acad. Sci., 10457-10461) as well as vascular dysfunction mediated by glucose in models of diabetes (Tilton et. al., 1997, J. Clin. Invest., 2192-2202).
VEGF is produced in cells in a number of isoforms including, VEGF205, VEGF189, VEGF165, and VEGF121, of which VEGF165 and VEGF121 are normally seen in the serum. The receptors for VEGF (e.g., KDR and Flt-1 are expressed on endothelial cells and interaction of the ligand, VEGF, and the receptors is responsible for the effects described above. Interruption of VEGF binding to its receptors, via antibodies or small molecules, would be an effective therapy for the treatment of diseases mediated by aberrant angiogenesis.